Genetic mapping of high caries experience on human chromosome 13

Background: Our previous genome-wide linkage scan mapped five loci for caries experience. The purpose of this study was to fine map one of these loci, the locus 13q31.1, in order to identify genetic contributors to caries.Methods: Seventy-two pedigrees from the Philippines were studied. Caries experience was recorded and DNA was extracted from blood samples obtained from all subjects. Sixty-one single nucleotide polymorphisms (SNPs) in 13q31.1 were genotyped. Association between caries experience and alleles was tested. We also studied 1,481 DNA samples obtained from saliva of subjects from the USA, 918 children from Brazil, and 275 children from Turkey, in order to follow up the results found in the Filipino families. We used the AliBaba2.1 software to determine if the nucleotide changes of the associated SNPs changed the prediction of the presence of transcription-binding site sequences and we also analyzed the gene expression of the genes selected based on binding predictions. Mutation analysis was also performed in 33 Filipino individuals of a segment of 13q31.1 that is highly conserved in mammals.Results: Statistically significant association with high caries experience was found for 11 markers in 13q31.1 in the Filipino families. Haplotype analysis also confirmed these results. In the populations used for follow-up purposes, associations were found between high caries experience and a subset of these markers. Regarding the prediction of the transcription-binding site, the base change of the SNP rs17074565 was found to change the predicted-binding of genes that could be involved in the pathogenesis of caries. When the sequence has the allele C of rs17074565, the potential transcription factors binding the sequence are GR and GATA1. When the subject carries the G allele of rs17074565, the potential transcription factor predicted to bind to the sequence is GATA3. The expression of GR in whole saliva was higher in individuals with low caries experience when compared to individuals with high caries experience (p = 0.046). No mutations were found in the highly conserved sequence.Conclusions: Genetic factors contributing to caries experience may exist in 13q31.1. The rs17074565 is located in an intergenic region and is predicted to disrupt the binding sites of two different transcription factors that might be involved with caries experience. GR expression in saliva may be a biomarker for caries risk and should be further explored. © 2013 Küchler et al.; licensee BioMed Central Ltd

Aquaporin 5 interacts with fluoride and possibly protects against caries

Aquaporins (AQP) are water channel proteins and the genes coding for AQP2, AQP5, and AQP6 are clustered in 12q13. Since AQP5 is expressed in serous acinar cells of salivary glands, we investigated its involvement in caries. DNA samples from 1,383 individuals from six groups were studied. Genotypes of eight single nucleotide polymorphisms covering the aquaporin locus were tested for association with caries experience. Interaction with genes involved in enamel formation was tested. The association between enamel microhardness at baseline, after creation of artificial caries lesion, and after exposure to fluoride and the genetic markers in AQP5 was tested. Finally, AQP5 expression in human whole saliva, after exposure to fluoride in a mammary gland cell line, which is known to express AQP5, and in Wistar rats was also verified. Nominal associations were found between caries experience and markers in the AQP5 locus. Since these associations suggested that AQP5 may be inhibited by levels of fluoride in the drinking water that cause fluorosis, we showed that fluoride levels above optimal levels change AQP5 expression in humans, cell lines, and rats. We have shown that AQP5 is involved in the pathogenesis of caries and likely interacts with fluoride

Role of estrogen related receptor beta (ESRRB) in DFN35B hearing impairment and dental decay

Background: Congenital forms of hearing impairment can be caused by mutations in the estrogen related receptor beta (ESRRB) gene. Our initial linkage studies suggested the ESRRB locus is linked to high caries experience in humans.Methods: We tested for association between the ESRRB locus and dental caries in 1,731 subjects, if ESRRB was expressed in whole saliva, if ESRRB was associated with the microhardness of the dental enamel, and if ESRRB was expressed during enamel development of mice.Results: Two families with recessive ESRRB mutations and DFNB35 hearing impairment showed more extensive dental destruction by caries. Expression levels of ESRRB in whole saliva samples showed differences depending on sex and dental caries experience.Conclusions: The common etiology of dental caries and hearing impairment provides a venue to assist in the identification of individuals at risk to either condition and provides options for the development of new caries prevention strategies, if the associated ESRRB genetic variants are correlated with efficacy. © 2014 Weber et al.; licensee BioMed Central Ltd

Whorl patterns on the lower lip are associated with nonsyndromic cleft lip with or without cleft palate

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect due to both genetic and environmental factors. Whorl lip print patterns are circular grooves on the central upper lip and/or the left and right lower lip. To determine if whorls are more common in families with CL/P than in controls, the Pittsburgh Orofacial Cleft Study collected lip prints from over 450 subjects, that is, individuals with CL/P, their relatives, and unrelated controls - from the U.S., Argentina, and Hungary. Using a narrow definition of lower-lip whorl, the frequency of whorls in the U.S. sample was significantly elevated in cleft individuals and their family members, compared to unrelated controls (14.8% and 13.2% vs. 2.3%; P=0.003 and 0.001, respectively). Whorls weremore frequent in CL/P families from Argentina than in CL/P families fromthe U.S. or Hungary. If these results are confirmed, whorl lip print patterns could be part of an expanded phenotypic spectrum of nonsyndromic CL/P. As such, they may eventually be useful in a clinical setting, allowing recurrence risk calculations to incorporate individual phenotypic information in addition to family history data. © 2009 Wiley-Liss, Inc

Sentinel phenotype for rubella embryopathy: time-space distribution in Brazil

The dyad comprising eye anomalies and congenital heart defects in the same newborn has been proposed as the best sentinel phenotype for the early detection of rubella embryopathy. Time-space birth prevalence distributions of the eye-heart dyad were described in 36 Brazilian hospitals from the Latin-American Collaborative Study of Congenital Anomalies - ECLAMC network, for the period 1994-2008. Seventy dyad cases observed among 554,531 births showed seasonal variation (Χ2 = 5.84; p < 0.05), suggesting an environmental etiology, with an increase in cases in October-March and acrophase in December. The secular distribution of dyad prevalence rates was consistent with the distribution of rubella cases in Brazil, showing a decrease from 1994 to 2004, followed by an increase until 2008. Two geographic clusters were identified, one with high and the other with low dyad prevalence. In the high prevalence cluster, a secular increase was observed, starting in 1999, matching the rubella epidemic waves observed in Brazil in 1998-2000 and 2006

Association of AXIN2 with non-syndromic oral clefts in multiple populations

We have previously shown the association of AXIN2 with oral clefts in a US population. Here, we expanded our study to explore the association of 11 AXIN2 markers in 682 cleft families from multiple populations. Alleles for each AXIN2 marker were tested for transmission distortion with clefts by means of the Family-based Association Test. We observed an association with SNP rs7224837 and all clefts in the combined populations (p = 0.001), and with SNP rs3923086 and cleft lip and palate in Asian populations (p = 0.004). We confirmed our association findings in an additional 528 cleft families from the United States (p < 0.009). We tested for gene-gene interaction between AXIN2 and additional cleft susceptibility loci. We assessed and detected Axin2 mRNA and protein expression during murine palatogenesis. In addition, we also observed co-localization of Axin2 with Irf6 proteins, particularly in the epithelium. Our results continue to support a role for AXIN2 in the etiology of human clefting. Additional studies should be performed to improve our understanding of the biological mechanisms linking AXIN2 to oral clefts. © 2012 International & American Associations for Dental Research